Obesity is a significant public health problem, which leads to many health-related comorbidities as well as increased morbidity and mortality. Weight loss of at least 5-10% of initial body weight has been shown in short-term trials to improve many obesity-related co-morbidities, and can be achieved through several strategies, including medical weight loss and surgical procedures; yet few studies have rigorously compared the effectiveness of these interventions directly. Furthermore, despite their effectiveness, surgical weight loss approaches are generally not recommended for patients with a BMI <35 kg/m2, regardless of the number or severity of comorbid conditions. Finally, because some surgical procedures, such as the Roux-en Y Gastric Bypass alters the anatomy of the gastrointestinal system and appear to affect its hormonal response to food intake, it is thought that different interventions may result in health improvements through different mechanisms. We hypothesize that a) early metabolic improvements are due to a combination of caloric restriction and changes in the gut-neuroendocrine axis, whereas b) later improvements are related to reductions in obesity and central adiposity. To investigate this hypothesis, we propose a pilot, 6-month, randomized controlled trial in patients with mild to moderate obesity (BMI 30-40 kg/m2) with three arms: 1) medical weight loss (low calorie diet of 800-1200 kcal/day), 2) Roux-en-Y gastric bypass and 3) laparoscopic adjustable gastric banding. To be eligible, patients must have type 2 diabetes (T2DM) and obstructive sleep apnea (OSA), chosen because they are associated with very high risk for cardiovascular complications and mortality. Our pilot study has the following Primary Specific Aims: 1) Assess the feasibility of recruiting, randomizing, delivering the interventions and following patients in a study including both medical weight loss and different surgeries; 2) Examine the comparative effectiveness of the interventions on T2DM and OSA; and 3) Explore the mechanisms for improvement in diabetes, using euglycemic and hyperglycemic clamps, and in sleep apnea, using physiologic characterization of sleep disordered breathing patterns. Additionally, in this pilot study we aim to gather valuable data for the conduct of a future more definitive study. To accomplish these aims, we have created a multi-disciplinary team of established researchers experienced in clinical trials, obesity, bariatric surgery, diabetes, sleep apnea and physiology. We propose state-of-the-art measurement techniques to assess our outcomes. We have partnered with various payers and a meal replacement manufacturer to ensure the feasibility of our proposed study. Ultimately, this line of research will help guide the choice of obesity therapy for patients with obesity-related co-morbidities. PUBLIC HEALTH RELEVANCE: Weight loss is effective in reducing many complications of obesity, with the majority of patients who undergo bariatric surgery having substantial improvements in their weight-related illnesses. We propose a pilot study in 45 subjects with mild to moderate obesity to compare how losing 10% of initial body weight via one of three common weight loss strategies (medical weight loss with a low calorie diet, Roux-en-Y gastric bypass surgery, and adjustable gastric banding) affects diabetes and sleep apnea. While we do not expect this pilot study to provide definitive answers, it will provide valuable information to design a larger trial which will help guide therapy for people with mild-moderate obesity and substantial co-morbidities.